Is CIC p.Leu2158fs (c.6470dup) pathogenic?

CIC p.Leu2158fs (c.6470dup) is classified Likely pathogenic in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). Very rare (popmax 6.93e-05%).

How common is CIC p.Leu2158fs (c.6470dup) in the general population?

CIC p.Leu2158fs (c.6470dup) is very rare (popmax 6.93e-05%) (gnomAD).

CIC p.Leu2158fs

c.6470dup · VCV4886520

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.93e-05%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen); NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.5	GERP 0.33, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.93e-05%

Overall 6.93e-05% 1/1,442,834 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CIC
Protein: p.Leu2158fs
Coding: c.6470dup
MANE Select: NM_005984 · reported on NM_001386298
Type: Duplication
Location: chr19:42293223 (GRCh38)
Structure: AlphaFold pLDDT 75.09

Full CIC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIC p.Leu2158Pro Uncertain significance ★ ⚠ same residue
CIC p.Pro2483_Leu2484insGlnAlaAlaProPro Uncertain significance ★★ same type
CIC p.Pro2507fs Uncertain significance ★★ same type
CIC p.Ala1975fs Likely pathogenic ★ same type
CIC p.Arg688fs Pathogenic ★ same type
CIC p.Asp2349fs Pathogenic ★ same type
CIC p.Cys397fs Likely pathogenic ★ same type
CIC p.Gly1425fs Pathogenic ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cic-p-leu2158fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown